E3 ubiquitin ligase NEDD4 promotes influenza virus infection by decreasing levels of the antiviral protein IFITM3

IFITM3 is critical for limiting the severity of influenza virus infections in humans and mice. Optimal antiviral activity of IFITM3 is achieved when it is present at high levels within cells. Our results indicate that the E3 ubiquitin ligase NEDD4 decreases baseline IFITM3 levels by ubiquitinating IFITM3 and promoting its turnover. Depleting NEDD4 from cells results in IFITM3 accumulation and greater resistance to infection by influenza viruses. Therefore, we have identified NEDD4 as a regulator of IFITM3 levels and as a novel drug target for preventing influenza virus and other IFITM3-sensitive virus infections.

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